Antipsychotic composition and method of treatment

ABSTRACT

A method for treating a serious psychotic mental illness includes the step of administering to a patient in need of such treatment a combination of (i) an α 2  -adrenergic receptor antagonist and (ii) a D 2  dopamine receptor antagonist. A pharmaceutical composition useful in the novel method includes an effective amount of the combination of the foregoing two ingredients together with a pharmaceutically acceptable carrier.

REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part application that claims benefit under 35U.S.C. 120 to Ser. No. 07/987,728 filed Dec. 9, 1992, now U.S. Pat. No.5,472,907, contents of which are incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to an antipsychotic composition and to amethod of treatment of patients suffering from serious psychotic mentalillness.

Conventional antipsychotic drugs, termed "typical antipsychotics," areeffective in improving symptoms of schizophrenia by acting as dopaminereceptor antagonists, more particularly D₂ dopamine receptorantagonists, which also are known as D₂ dopamine receptor blockadingagents. Such activity decreases the activity of the brainneurotransmitter dopamine. See Snyder, Am. J. Psychiatry 133: 197-202(1976); Creese et al., Science 192:481-83 (1976); Seeman et al., Nature251:717-19 (1976). Typical antipsychotics include those drugs known as"typical neuroleptics," exemplary of which are chlorpromazine,fluphenazine, trifluoperazine and haloperidol, among others. But asignificant number of patients suffering from schizophrenia have provenresistant to treatment with typical neuroleptics.

It is known that clozapine, an "atypical neuroleptic," that is, anantipsychotic neuroleptic which produces few or no extrapyramidal sideeffects ("EPS's") and does not cause catalepsy in animal models, iseffective in treating patients suffering from schizophrenia who hadshown poor response to other drugs. Kane et al., Arch. Gen. Psychiatry45:789-96 (1988). The mechanism of action of clozapine includes α₂-adrenergic receptor antagonism, in addition to a dopamine-blockadingaction which is characteristic of typical antipsychotic neuroleptics.See Pickar et al., Arch. Gen. Psychiatry 49:345-53 (1992) ("Pickar etal.").

Use of clozapine is associated with severe side effects, however,including agranulocytosis, seizures and adverse cardiovascular effects.See, for example, THE PHYSICIANS' DESK REFERENCE (1992), pages 1942-45;Griffith et al., Lancet 2:657 (1979).

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide aneffective method of treatment for patients suffering from seriouspsychotic mental illness who have not responded adequately to treatmentwith "typical" antipsychotics, such as antipsychotic neuroleptics.

It is another object of the present invention to provide a method oftreatment which does not have the severe side effects associated withthe administration of clozapine.

It is yet another object of the present invention to providepharmaceutical compositions useful in the foregoing methods oftreatment.

In accomplishing the foregoing objectives, there has been provided, inaccordance with one aspect of the present invention, a method fortreating a serious psychotic mental illness comprising the step ofadministering to a patient in need of such treatment a combination of(i) an α₂ -adrenergic receptor antagonist and (ii) a D₂ dopaminereceptor antagonist. In a preferred embodiment, the α₂ -adrenergicreceptor antagonist is idazoxan.

In accordance with another aspect of the present invention there isprovided a pharmaceutical composition comprising a combination of (i) anα₂ -adrenergic receptor antagonist, (ii) a D₂ dopamine receptorantagonist, (iii) a pharmaceutically acceptable carrier, wherein theamount of ingredients (i) and (ii) is therapeutically effective againstserious psychotic mental illness.

Other objects, features and advantages of the present invention willbecome apparent to those skilled in the art from the following detaileddescription. It is to be understood, however, that the detaileddescription and specific examples, while indicating preferredembodiments of the present invention, are given by way of illustrationand not limitation. Many changes and modifications within the scope ofthe present invention may be made without departing from the spiritthereof, and the invention includes all such modifications.

BRIEF DESCRIPTION OF THE DRAWING

The present invention can be understood more readily by reference to theaccompanying drawing, by which:

FIG. 1 is a bar graph that depicts total symptoms, measured in relationto the Brief Psychiatric Rating Scale (BPRS), in the context oftreatment with fluphenazine, with fluphenazine plus idazoxan, and withfluphenazine after discontinuation of idazoxan. An asterisk (*) denotesa probability (p) <0.05 in a Duncan's Multiple Range post hoc test.

FIG. 2 presents bar graphs which relate, respectively, BPRS negative (A)and positive (B) subscale values corresponding to treatment withfluphenazine prior to addition of idazoxan, with both compounds, andwith fluphenazine after administration of idazoxan was discontinued.Asterisk (*): F(2,10)=3.50; p=0.07.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It has been discovered that the administration of an α₂ -adrenergicreceptor antagonist unexpectedly enhances the therapeutic effect oftypical antipsychotic neuroleptics. Thus, the combined administration ofan α₂ -adrenergic receptor antagonist and a typical antipsychoticneuroleptic has been found to be an effective substitute for clozapinein treating patients suffering from serious psychotic mental illness.The present invention provides an improved treatment for patientssuffering from serious psychotic mental illness who have provenresistant to treatments with known typical antipsychotic neurolepticsalone, which treatment is not characterized by the harmful side effectsarising from treatment with clozapine.

The term "serious psychotic mental illness" denotes conditions in whichdelusions and/or hallucinations, along with other negativesymptomatology, are present. See Diagnostic and Statistical Manual ofMental Disorders, 3rd rev'sd ed., 1993, ("DSM IIIR") and Diagnostic andStatistical Manual of Mental Disorders, 4th edition, 1994 ("DSM IV"),American Psychiatric Association, Committee on Nomenclature andStatistics (Washington, D.C., American); and Pickar et al.

Typical symptoms associated with serious psychotic mental illnessesinclude, inter alia, the sudden onset of delusions, or hallucinations,disorganized speech (e.g., frequent derailment or incoherence), grosslydisorganized or catatonic behavior, paranoia, and major manic,depressive or mixed episodes. Illustrative of serious psychotic mentalillnesses are schizophrenia and schizoaffective illnesses, briefpsychotic disorders which involve the sudden onset of delusions, orhallucinations, disorganized speech (e.g. frequent derailment orincoherence), or grossly disorganized or catatonic behavior. Briefpsychotic disorders are not schizoaffective disorders. Individualsexperiencing brief psychotic disorders typically experience emotionalturmoil or overwhelming confusion, may have rapid shifts from oneintense affect to another, and typically exhibit poor judgement,cognitive impairment, or actions based upon delusions.

Within the context of the present invention, "serious psychotic mentalillness" also includes Bipolar I disorders typically manifested byindividuals who have previously experienced at least one manic episodeor mixed episode and who later manifest a manic, hypomanic, mixed, or amajor depressive episode which cause clinically significant distress orimpairment in social, occupational or other important areas offunctioning. The mood symptoms of Bipolar I disorders are not due to thedirect physiological affects of substance abuse or medication and arenot better accounted for by schizoaffective disorder and are notsuperimposed on schizophrenia, schizophreniform disorder, delusionaldisorder, or psychotic disorder not otherwise specified.

Serious psychotic mental illness pertains also to paranoid personalitydisorders wherein an individual manifests a pattern of pervasivedistrust and suspiciousness of others such that the motives of othersare interpreted as malevolent. Schizoid personality disorders andschizotypal personality disorders also fall within the parameters of thepresent invention. The essential feature of schizoid personalitydisorders is a pervasive pattern of detachment from social relationshipsand a restricted range of expression of emotions in interpersonalsettings. Schizotype personality disorders manifest a pervasive patternof social and interpersonal deficits marked by acute discomfort with,and reduced capacity for close relationships as well as by cognitive orperceptual distortions in eccentricities of behavior.

In sum, serious psychotic mental illnesses include, inter alia,Schizophreniform Disorder, Schizoaffective Disorder, SeverSchizoaffective Disorder with Psychotic Features, Bipolar I Disorderswith a Single Manic Episode, Sever Bipolar I Disorders with PsychoticFeatures, Major Depressive Disorders Manifesting a Single Episode,Severe Major Depressive Disorders with Psychotic Features, Bipolar IDisorders Manifesting a Mixed Most Recent Episode, Severe Bipolar IDisorders with Psychotic Features, Brief Psychotic Disorders, PsychoticDisorders NOS, Paranoid Personality Disorders, Schizoid PersonalityDisorders, Schizophrenia, Schizotypal Personality Disorders withSedative, Hypnotic, or Anxiolytic Manifestations, Major DepressiveDisorders with Recurrent Episodes, and Psychotic Disorders due toSpecific General Medical Conditions.

Preferably, the α₂ -adrenergic receptor antagonist utilized according tothe invention is a selective antagonist, i.e., a drug whose principalpharmacological effect in vitro is antagonism of α₂ -adrenergicreceptors. Any additional pharmacological effects should be minor incomparison to this principal effect.

A particularly preferred α₂ -adrenergic receptor antagonist for useaccording to the invention is idazoxan[(±)-2-(1,4-benzodioxan-2-yl)-2-imidazoline]. Idazoxan is a highlyselective α₂ -adrenergic receptor antagonist. See Doxey et al., Arch.Pharmacol. 325:136-44 (1984). Other useful α₂ -adrenergic receptorantagonists include yohimbine, ethoxy-idazoxan, fluperoxan andatipamezole.

Non-limiting examples of antipsychotic neuroleptics useful according tothe invention include thiopropazate, chlorpromazine, triflupromazine,mesoridazine, piperacetazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chlorprathixene,thiothixene, haloperidol, bromperidol, loxapine and molindone.

In a preferred embodiment of the method according to the invention, theα₂ -adrenergic receptor antagonist is administered to a patientpresently undergoing chronic neuroleptic treatment. This permitsassessment of the effect of the neuroleptic prior to the administrationof the α₂ -adrenergic receptor antagonist. The two compounds also can beadministered together at the beginning of treatment, if desired.

Preferred dosages of the α₂ -adrenergic receptor antagonist according tothe invention range from about 60 to 120 mg/day. Preferred dosages ofthe typical antipsychotic neuroleptic are routinely determined, andrange from about 100 to about 900 mg/day chlorpromazine equivalents. SeeSnyder, supra, and Seeman, supra.

In one embodiment of the present invention, both the α₂ -adrenergicreceptor antagonist and the antipsychotic neuroleptic can beadministered in separate form. The two compounds can also beadministered in a single pharmaceutical composition, in combination withknown pharmaceutically acceptable carriers. Such pharmaceuticalcompositions thus constitute another aspect of the present invention.These compositions may be prepared from conventional materials by knownprocedures.

Compositions within the present invention can be adapted for oral orparenteral administration, as well as for enteral administration orallyor through mucus membranes, that is, intranasally, sublingually,buccally or rectally.

Compositions for oral administration include capsules, tablets,dispersible powders, granules, syrups, elixirs and suspensions. Thesecompositions can contain one or more conventional adjuvants, such assweetening agents, flavoring agents, coloring agents and preservingagents.

Tablets can contain the active ingredients in a mixture withconventional pharmaceutically acceptable excipients. These include inertcarriers, such as calcium carbonate, sodium carbonate, lactose, andtalc; granulating and disintegrating agents, such as starch and alginicacid; binding agents such as starch, gelatin acacia; and lubricatingagents, such as magnesium stearate, stearic acid and talc. Tablets maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over a longer period of time.

Capsules may contain the active ingredients alone or an admixture withan inert solid carrier, such as calcium carbonate, calcium phosphate orkaolin. Similarly, suspensions, syrups and elixirs may contain theactive ingredients in mixture with any of the conventional excipientsutilized in the preparation of such compositions. This includessuspending agents such as methylcellulose, tragacanth and sodiumalginate; wetting agents such as lecithin, polyoxyethylene stearate orpolyoxyethylene sorbitan monoleate; and preservatives.

The present invention is described further by reference to thefollowing, illustrative examples.

EXAMPLE 1 Administration of Idazoxan in Combination with Fluphenazine

Six hospitalized patients (two female, four male) who met DSM-IIIRcriteria for schizophrenia and had no medical or neurologic illnessgranted informed consent for a double-blind, placebo-controlledpharmacologic study during which idazoxan could be added to ongoingfluphenazine treatment. These patients also met criteria for treatmentresistance to typical neuroleptics, to wit: (1) drug intolerance,defined as either significant tardive dyskinesia or EPSs, or (2) historyof being refractory to treatment, defined as a lack of satisfactoryclinical response to at least two different antipsychotic drugs given inadequate doses and for adequate periods.

Prior to treatment with idazoxan, patients were medicated with blindedcapsules of fluphenazine hydrochloride (treatment duration: 56.5±17.4days; mean daily dose: 27.9±11.4 mg) and placebo; patients wereclinically stable on fluphenazine and placebo for at least four weeksprior to the addition of idazoxan, and no changes in fluphenazine dosagewere made for at least four weeks prior to or during idazoxan treatment.Benztropine mesylate (in blinded capsules) was prescribed as indicatedfor EPSs; doses were unchanged for at least four weeks prior to theaddition of idazoxan and throughout the study.

Idazoxan, also administered as blinded capsules, was started at aninitial dose of 20 mg bid and increased by increments of 20 mg over twoweeks to a maintenance dose of 120 mg/day. (One patient experienced onenight of insomnia which responded rapidly to dosage adjustment ofidazoxan; this patient was maintained instead of 100 mg/day for thestudy duration.)

All patients were treated with idazoxan at maintenance doses for 4-6weeks (32.6±11.4 days). Idazoxan was then tapered by reductions of 20mg/day over two weeks. Following discontinuation of idazoxan, patientswere studied for three additional weeks (23.2±6.3 days) on fluphenazine.All medications were administered under double blind conditions.Patients received placebo capsules which were identical in appearance toblinded idazoxan and fluphenazine capsules before, during and afteridazoxan treatment.

Physicians who were blind to medication phase and who had no knowledgeregarding the initiation and discontinuation of idazoxan treatmentcompleted both the Brief Psychiatric Rating Scale, defined in Overall etal., Psychol. Rep. 10:799-812 (1961), and the Simpson NeurologicalRating Scale, defined in Simpson et al., Acta Psychiatr. Scand. 212(suppl'mt): 9-11 (1970), for drug side effects weekly for all patients.Additionally, blood samples were collected for plasma fluphenazinelevels from five of six patients via standard venipuncture at 7:30 a.m.following overnight fast, during treatment with fluphenazine beforeaddition of idazoxan, and during combined treatment with fluphenazineand idazoxan, after at least two weeks of stable medication doses.

Rating scale total scores were averaged from the three weeks immediatelypreceding idazoxan treatment, the last four weeks of maintenanceidazoxan treatment, and the three weeks immediately following idazoxandiscontinuation for each patient. Differences in rating scores wereanalyzed as indicated in Table 1 and FIGS. 1-2.

                                      TABLE 1                                     __________________________________________________________________________    Behavioral Ratings During Fluphenazine Treatment, Combined Idazoxan and       Fluphenazine Treatment, and Fluphenazine Treatment After Discontinuation      of Idazoxan (N = 6).sup.a                                                                                          Repeated Measures                                             Idazoxan and    ANOVA                                    Rating Scale Fluphenazine.sup.b                                                                    Fluphenazine                                                                          Fluphenazine.sup.c                                                                    F    P                                   __________________________________________________________________________    BPRS total   57.4 + 6.2                                                                            50.3 + 4.2*                                                                           58.1 + 8.0                                                                            4.16 0.05                                BPRS positive symptoms                                                                      8.5 + 3.2                                                                            7.4 + 1.9                                                                              9.3 + 1.4                                                                            1.22 0.33                                BPRS negative symptoms                                                                     10.7 + 2.4                                                                            9.4 + 1.7                                                                             10.6 + 2.0                                                                            3.50 0.07                                SNS total    12.9 + 1.6                                                                            12.2 + 1.2                                                                            12.9 + 1.5                                                                            1.33 0.30                                __________________________________________________________________________     .sup.a BPRS indicates Brief Psychiatric Rating Scale; SNS, Simpson            Neurological Scale; ANOVA, Analysis of Variance, Values are expressed as      mean + SD; df = 2,10 for all comparisons.                                     .sup.b prior to addition of idazoxan                                          .sup.c after discontinuation of idazoxan                                      *p < 0.05 vs fluphenazine treatment before the addition and after             discontinuation of idazoxan, Duncan's Multiple Range Test                

As is apparent from Table 1 and from FIG. 1, combined administration ofidazoxan and fluphenazine resulted in significant decreases in mean BPRStotal score when compared to fluphenazine treatment alone, both beforeand after addition of idazoxan. Negative symptoms measured by the BPRSnegative symptoms subscale were similarly reduced by theidazoxan-fluphenazine combination, to a degree which approachedstatistical significance (Table 1 and FIG. 2A). Differences in positivesymptoms as measured by the BPRS positive symptoms subscale were notstatistically significant (Table 1); however, three out of six patientsshowed clinically significant reductions in positive symptoms (FIG. 2B).Adding idazoxan to fluphenazine did not result in significant changes inextrapyramidal symptoms as measured by the Simpson Neurological RatingScale, nor did it result in increases in plasma fluphenazine levels(mean plasma fluphenazine without idazoxan: 1.66±0.56 ng/ml; withidazoxan: 1.80±0.74 ng/ml; T=-0.5, df=4, p<0.7). With the exception ofone patient who experienced transient insomnia, idazoxan was welltolerated by patients, who experienced no clinically significant sideeffects.

Thus, it is apparent that the addition of idazoxan to typicalneuroleptic therapy can improve treatment response intreatment-resistant patients suffering from schizophrenia. All sixpatients showed some improvement in symptoms with the addition ofidazoxan, and five had worsening of symptoms upon idazoxandiscontinuation. The most significant improvement occurred in thenegative symptoms subscale of the BPRS, although improvement in positivesymptoms occurred in three of the patients studied. The reduction inBPRS total score observed with idazoxan treatment is comparable to thereduction in BPRS total score of a similar group of patients treated fora comparable time period with moderate doses of clozapine [see Pickar etal., supra].

EXAMPLE 2 Formulations

Pharmaceutical compositions according to the present invention caninclude the α₂ -adrenergic receptor antagonist and the D₂ dopaminereceptor antagonist in various proportions. For example, a tablet caninclude trifluoperazine and idazoxan in the proportions 5 mg: 40-80 mg.A capsule can include chlorpromazine and idazoxan in the proportions100-200 mg: 40 mg.

What is claimed is:
 1. A method for treating a serious psychotic mentalillness comprising the step of administering to a patient in need ofsuch treatment a therapeutically effective amount of a combination of(i) an α₂ -adrenergic receptor antagonist and (ii) a D₂ dopaminereceptor antagonist in a pharmaceutically acceptable carrier.
 2. Amethod as claimed in claim 1, wherein said α₂ -adrenergic receptorantagonist (i) is selected from the group consisting of idazoxan,yohimbine, ethoxy-idazoxan, fluperoxan and atipamezole.
 3. A method asclaimed in claim 2 wherein said α₂ -adrenergic receptor antagonist (i)is idazoxan.
 4. A method as claimed in claim 1, wherein said D₂ dopaminereceptor antagonist (ii) is an antipsychotic neuroleptic drug.
 5. Amethod as claimed in claim 4, wherein said antipsychotic neurolepticdrug is selected from the group consisting of thiopropazate,chlorpromazine, triflupromazine, mesoridazine, piperacetazine,thioridazine, acetophenazine, fluphenazine, perphenazine,trifluoperazine, chlorprathixene, thiothixene, haloperidol, bromperidol,loxapine, and molindone.
 6. A method as claimed in claim 1, wherein saidα₂ -adrenergic receptor antagonist (i) is administered in an amount fromabout 60 to 120 mg/day.
 7. A method as claimed in claim 1, wherein saidserious psychotic mental illness is schizoprenia.
 8. A pharmaceuticalcomposition comprising a combination of (i) an α₂ -adrenergic receptorantagonist, (ii) a D₂ dopamine receptor antagonist, and (iii) apharmaceutically acceptable carrier, wherein the amount of saidingredients (i) and (ii) is therapeutically effective against seriouspsychotic mental illness.
 9. A composition as claimed in claim 8,wherein said α₂ -adrenergic receptor antagonist (i) is selected from thegroup consisting of idazoxan, yohimbine, ethoxy-idazoxan, fluperoxan andatipamezole.
 10. A composition as claimed in claim 9, wherein said α₂-adrenergic receptor antagonist (i) is idazoxan.
 11. A composition asclaimed in claim 8, wherein said D₂ dopamine receptor antagonist (ii) isan antipsychotic neuroleptic drug.
 12. A composition as claimed in claim11, wherein said antipsychotic neuroleptic drug is selected from thegroup consisting of thiopropazate, chlorpromazine, triflupromazine,mesoridazine, piperacetazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chlorprathixene,thiothixene, haloperidol, bromperidol, loxapine, and molindone.
 13. Amethod for treating a serious psychotic mental illness comprising thestep of administering to a patient in need of such treatment atherapeutically effective amount of a combination of (i) an α₂-adrenergic receptor antagonist and (ii) a D₂ dopamine receptorantagonist in a pharmaceutically acceptable carrier, wherein saidserious psychotic mental illness is selected from the group consistingof Schizophreniform Disorder, Severe Schizoaffective Disorder withPsychotic Features, Bipolar I Disorders with a Single Manic Episode,Severe Bipolar I Disorders with Psychotic Features, Major DepressiveDisorders Manifesting a Single Episode, Severe Major DepressiveDisorders with Psychotic Features, Bipolar I Disorders Manifesting aMixed Most Recent Episode, Severe Bipolar I Disorders with PsychoticFeatures, Brief Psychotic Disorders, Psychotic Disorders NOS, ParanoidPersonality Disorders, Schizoid Personality Disorders, SchizotypalPersonality Disorders with Sedative, Hypnotic, or AnxiolyticManifestations, Major Depressive Disorders with Recurrent Episodes, andPsychotic Disorders due to Specific General Medical Conditions.
 14. Themethod as claimed in claim 13, whereto said α₂ -adrenergic receptorantagonist (i) is one or more selected from the group consisting ofidazoxan, yohimbine, ethoxy-idazoxan, fluperoxan and atipamezole, andwherein said D₂ dopamine receptor antagonist (ii) is one or moreselected from the group consisting of thiopropazate, chlorpromazine,triflupromazine, mesoridazine, piperacetazine, thioridazine,acetophenazine, fluphenazine, perphenazine, trifluoperazine,chlorprathixene, thiothixene, haloperidol, bromperidol, loxapine, andmolindone.
 15. The method as claimed in claim 13, wherein said α₂-adrenergic receptor antagonist (i) is administered in an amount fromabout 60 to 120 mg/day.